**2. Diabetes mellitus-associated vascular complications**

Hyperglycemia triggers damage to the vasculature and thus, leads to the failure of various organs including kidney, heart, retina of eyes and nerves; usually develop after many years of diabetes. This gives rise to the development of vascular complications which are categorized into micro- and macrovascular complications. Microvascular disease or microangiopathy is actually the thickening of walls of small blood vessels so that they bleed and leakage of protein occurs. This narrowing of blood vessels results in decreased blood flow and impairment of oxygen flow throughout the body which leads to the damage of tissues or organs that are extremely sensitive to oxygen levels i.e., kidney cells, nerve cells and retina. On the other hand, macrovascular disease or macroangiopathy is the disease of large blood vessels due to clot formations that further results in the decreased blood flow all through the body. This may cause heart diseases, peripheral vascular diseases or stroke. Both micro- and macrovascular complications are the result of hyperglycemia and it seems that they both may be interconnected but who precedes whom or whether they progress together, it is not clear. Complications of T2DM keep on increasing due to increasing burden of diabetes, thus deteriorating the quality of human life. Smoking, age factor, increased weight, lack of physical activity and high-fat diet are the common risk factors to diabetes complications. Now-a-days diabetic kidney disease (DKD) or DN and diabetic retinopathy (DR) are among the most frequent complications of diabetes. Improved and maintained glycemic control may reduce risk of some of the diabetic complications, but it is not the only factor which, if under control, may reduce the progression of all vascular complications. In this segment, we have elaborated two major microvascular complications of diabetes, i.e., DN and DR.

#### **2.1 Diabetic nephropathy**

Diabetic nephropathy is the major microvascular complication of diabetes affecting 20–30% of patients with type 2 diabetes mellitus [6], which weaken the quality of life leading to increased morbidity and mortality. Symptoms of DN are less evident in the early years of diabetes, usually develops after many years of diabetes. In India approximately 48% cases of CKD are caused by diabetes [7].

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*Diabetes Microvascular Complications: An Overview of Epigenetic Modifications*

DN is defined as a clinical syndrome characterized by persistent proteinuria, a moderate deterioration of eGFR and an increasing arterial blood pressure [8]. Being the foremost cause of end-stage renal disease (ESRD), it results in considerable morbidity and mortality and incurs massive burden of cost on patient and the society as well. Pathways, specifically renin-angiotensin-aldosterone system (RAAS), have been known to play a central role in the development and progression of nephropathy which eventually triggers numerous inflammatory factors directing to the development of fibrosis in the kidney, hypertension/hyperfilteration in the glomerulus and increased permeability to macromolecules leading to proteinuria [9]. It has been seen that some patients with good glycemic control may develop DN at later stages and patients with poor glycemic control may not always develop DN. This may partly be due to genetic predisposition among various ethnic populations. Presence of diabetic nephropathy within families and the large differences in its incidence among diabetic populations with different ethnicity suggests the contribution of several genetic and epigenetic factors in the development and progression of DN. Till date several candidate genes, that are susceptible to DN, have been recognized with the advancements of molecular techniques via linkage studies, GWAS or candidate gene studies. The important candidate genes includes ADIPOQ [10] and ACACβ [11] from lipid metabolism, GCKR [12] and TCF7L2 [13] from glucose metabolism, transforming growth factor-β1 (TGF-β1) involved in inflammation [14], genes associated with angiogenesis i.e., VEGF-A [15] and RAAS genes i.e., ACE [16] and AGTR1 [17], and recently SLC12A3 [18] whose various polymorphisms are reported to be associated with DN. Genes involved in RAAS have been most extensively investigated in the context of DN. Among RAAS genes, angiotensin converting enzyme (ACE) gene is found to be strongly correlated with DN. For this reason, ACE inhibitors and angiotensin receptor blockers (ARBs) are the first line of drugs for the treatment of diabetic nephropathy that aims to reduce proteinuria. Though these drugs have shown to reverse the progression of albuminuria from macroalbuminuria or microalbuminuria to normoalbuminuria [19], thereby slows down the progression of disease, but are not able to provide a stable renoprotective effect. The response of DN patients to ACE inhibitors or ARBs alone or in combination is also not uniform despite several studies. Moreover, there are some limitations regarding their usage based on particular patient to be treated. Hence, these drugs along with strict glycemic control contribute to some degree of renoprotection, but not complete. Therefore, it is the urge to discover new pathways leading to the development of more specific therapies/treatments to help DN

Diabetic retinopathy is a medical condition where damage to retina, as a result of high glucose, occurs. It is the most frequent cause of blindness in patients with diabetes. Patients with DR usually does not develop any major symptoms at an early stage but during later stages physiological and metabolic abnormalities can appear leading to blindness, if left untreated. The risk factors associated with DR includes high blood glucose [20], duration and type of diabetes [21], high B.P. [22] and, lipids [23]. Presently it is being diagnosed with the identification of microvascular lesions in the retina. It has been differentiated clinically in 2 categories on the basis of ophthalmic observation: proliferative DR (PDR), the advance stage and; non-proliferative DR (NPDR), the early stage. NPDR can be identified by fundus where hard exudates, microaneurysms or hemorrhages are seen. NPDR is further categorized into mild, moderate and severe NPDR. On the other hand, detection of retinal neovascularization confirms PDR. The risk of progression of DR can

*DOI: http://dx.doi.org/10.5772/intechopen.94642*

patients and improving their life.

**2.2 Diabetic retinopathy**

#### *Diabetes Microvascular Complications: An Overview of Epigenetic Modifications DOI: http://dx.doi.org/10.5772/intechopen.94642*

DN is defined as a clinical syndrome characterized by persistent proteinuria, a moderate deterioration of eGFR and an increasing arterial blood pressure [8]. Being the foremost cause of end-stage renal disease (ESRD), it results in considerable morbidity and mortality and incurs massive burden of cost on patient and the society as well. Pathways, specifically renin-angiotensin-aldosterone system (RAAS), have been known to play a central role in the development and progression of nephropathy which eventually triggers numerous inflammatory factors directing to the development of fibrosis in the kidney, hypertension/hyperfilteration in the glomerulus and increased permeability to macromolecules leading to proteinuria [9]. It has been seen that some patients with good glycemic control may develop DN at later stages and patients with poor glycemic control may not always develop DN. This may partly be due to genetic predisposition among various ethnic populations. Presence of diabetic nephropathy within families and the large differences in its incidence among diabetic populations with different ethnicity suggests the contribution of several genetic and epigenetic factors in the development and progression of DN. Till date several candidate genes, that are susceptible to DN, have been recognized with the advancements of molecular techniques via linkage studies, GWAS or candidate gene studies. The important candidate genes includes ADIPOQ [10] and ACACβ [11] from lipid metabolism, GCKR [12] and TCF7L2 [13] from glucose metabolism, transforming growth factor-β1 (TGF-β1) involved in inflammation [14], genes associated with angiogenesis i.e., VEGF-A [15] and RAAS genes i.e., ACE [16] and AGTR1 [17], and recently SLC12A3 [18] whose various polymorphisms are reported to be associated with DN. Genes involved in RAAS have been most extensively investigated in the context of DN. Among RAAS genes, angiotensin converting enzyme (ACE) gene is found to be strongly correlated with DN. For this reason, ACE inhibitors and angiotensin receptor blockers (ARBs) are the first line of drugs for the treatment of diabetic nephropathy that aims to reduce proteinuria. Though these drugs have shown to reverse the progression of albuminuria from macroalbuminuria or microalbuminuria to normoalbuminuria [19], thereby slows down the progression of disease, but are not able to provide a stable renoprotective effect. The response of DN patients to ACE inhibitors or ARBs alone or in combination is also not uniform despite several studies. Moreover, there are some limitations regarding their usage based on particular patient to be treated. Hence, these drugs along with strict glycemic control contribute to some degree of renoprotection, but not complete. Therefore, it is the urge to discover new pathways leading to the development of more specific therapies/treatments to help DN patients and improving their life.
